Leishmaniasis is a disease common in tropical and sub-tropical countries, including India. Current studies suggest that nitric oxide (NO) and peroxynitrite are crucial for elimination of the Leishmania parasites. Rural populations in India use turmeric abundantly in their daily life: as a spice, as a component of cosmetics, as an anti-inflammatory agent and other medications, and as a household topical remedy for minor injuries including insect bites. However, one of the major active principles in turmeric is curcumin, an inhibitor of nitric oxide production and a scavenger of nitric oxide and superoxide anions. Our laboratory has found that curcumin inhibits the gene expression of inducible nitric oxide synthase (iNOS) in vifro and in vivo in a bacterial lipopolysaccharide induction system. It also inhibits the activation of the transcription factor nuclear factor kappaB and the cytokines, tumor necrosis factor-alpha and interleukin-1beta, molecules that play roles in regulating iNOS gene expression. Moreover, curcumin enhances the production ofinterleukin-4, an iNOS down-regulating cytokine, by Leishmania-activated lymphocytes. Thus, we hypothesize that prolific use of curcumin may lead to exacerbation of leishmaniasis. This is supported by preliminary studies which indicates it exacerbates cutaneous infection in the footpad and increase infection in macrophage cell lines. Our long-term objective is to determine whether oral or topical application of curcumin affects the outcome of Leishmania infection in the populations at risk. In this proposal, we will evaluate the effect of curcumin on NO-mediated parasite killing, and the production of iNOS and iNOS-inducing cytokines in Leishmania-infected macrophages and in mice. Whereas the Indian population consumes large amounts of curcumin, the Western populations also use antioxidants or anti-inflammatories as dietary supplements and in daily skin care products. Although these compounds may potentially protect against certain aging conditions and autoimmunity, they may also inhibit the action of free radicals and cell- mediated immunity that are crucial for protection against many pathogens. Presently, only limited studies addressing this area have been performed. Our proposal fills this gap of knowledge.